Burden of upper gastrointestinal cancers in the east of Golestan province (Golestan cohort study)

Abstract Background Cancers, especially Upper Gastrointestinal Cancers (UGCs), pose a substantial burden on society, particularly in developing nations. Golestan province, Iran, is known for its high UGC rates globally. Aims This study delves into the disease burden of UGCs in the eastern part of Golestan province. Methods and Results This study was conducted using the results of the Golestan cohort study. 2711 patients participating in this cohort, who visited Atrak Clinic during 2001–2020, participated in this study. After excluding patients with incomplete records, 2481 patients were included in the study. To compute the metrics of years of life lost (YLL), years of life lived with disability (YLD), and disability‐adjusted life years (DALY), we utilized the World Health Organization's standard life table, stratified by age and gender. The majority of UGC patients in our study were married (81.8%), had limited formal education (82.6%), and were predominantly male (61.1%). A substantial proportion resided in suburban areas (85.8%), and over half of the patients (52%) reported a history of drug addiction. The mean age at diagnosis for men was 65.76 years with a standard deviation of 11.34, while for women, it was 64.38 years with a standard deviation of 11.66. Regarding disease impact, YLL, YLD, and DALY for men were 21 240, 1956, and 23 196 (307.8 per 100 000), respectively. For women, these figures were 15 609 for YLL, 1367 for YLD, and 16 976 (223.1 per 100 000) for DALY. Conclusion After the increasing trend of the burden of UGCs in Golestan province in the early years of the study, this rate has been decreasing in recent years. Effective strategies necessitate collaborative efforts across various sectors to alleviate this burden, focusing on preventive measures, timely diagnosis, and well‐coordinated therapeutic interventions.


| INTRODUCTION
The global disease landscape has shifted toward non-communicable diseases, with the primary drivers of this transformation being urbanization and demographic shifts within the population. 1 Currently, non-communicable diseases are the main cause of death worldwide. 2Cancers rank among the most prevalent noncommunicable diseases and stand as the leading cause of mortality in almost 50 high-income nations.Notably, lung, liver, stomach, colorectal, breast, and cervical cancers feature prominently among the top ten causes of cancer-related fatalities worldwide. 1In 2019, there were approximately 23.6 million newly diagnosed cases and 10 million cancer-related deaths worldwide.Among the 22 groups of diseases and injuries in the global burden of disease study GBD 2019, cancer ranked second globally after cardiovascular diseases in terms of mortality, years of life lost (YLL), and disability-adjusted life year (DALY). 3atistics reveal that nearly three-quarters of non-communicable disease-related mortalities occur in low-and middle-income nations. 2 For example, in the Eastern Mediterranean Region, about 60% of deaths are attributed to non-communicable diseases. 4It is expected that this ratio will increase to 70% by 2030. 5Furthermore, the heightened prevalence of risk factors associated with non-communicable diseases, including physical inactivity, obesity, tobacco use, and the consumption of foods rich in salt, sugar, and fat, has raised significant concerns in these regions. 4In Iran, the rise of non-communicable diseases has evolved into a substantial challenge.In 2019, these diseases led to the loss of 508 326 lives, marking an 88% increase from the figures observed in 1990.The number of premature deaths attributed to the four primary non-communicable diseases amounted to 66 818 in 1990, but by 2019, this number had surged significantly to 893 100 cases. 6Breast, colorectal and stomach cancers were the most prevelant cancers in Iran in 2016 and it is anticipated that they will remain the leading types of cancers in the country through 2025. 7strointestinal cancers (GCs) reduce health-related quality of life due to their aggressive nature and treatment complexity. 8Moreover, aligning with the objectives set forth in Sustainable Development Goal (SDG) 3.4, Iran is striving to reduce the percentage of premature deaths to 11.6% by 2025.However, this target appears challenging to attain given the current circumstances characterized by unhealthy lifestyles, a high disease burden, and inadequate investments in preventive measures, among other factors. 6lestan province in northern Iran is known as a high-risk area for GCs. 9 Controlling the high incidence of upper gastrointestinal cancers (UGCs) in the northern regions of Iran requires the implementation of corrective interventions.These interventions should cover the areas of prevention, early detection, treatment, and palliative care. 10e design and implementation of these interventions requires the existence of effective evidence regarding the incidence, prevalence and burden of these cancers.Few studies have been conducted in Iran regarding the long-term status of UGCs.This study was conducted with the aim of investigating the burden UGCs in Golestan province.

| METHODS
This study was conducted using the data of the Golestan cohort.The Golestan cohort study was conducted in 1997 by the Digestive Diseases Research Institute (DDRI) of Tehran University of Medical Sciences.After that, in 2007, the main study of the Golestan cohort was conducted.The primary objective of this cohort was to identify the factors contributing to the high incidence of esophageal cancer among individuals aged 40-75 years in regions with a high prevalence of gastrointestinal tract cancers, specifically Gonbad and Kalaleh cities in Golestan province.The cohort comprised randomly selected individuals from both urban and rural areas within these two cities, with 10 032 residents from urban areas and 40 013 residents from rural areas registered for the study. 11,12e data collected in Golestan cohort includes, demographic characteristic, lifestyle information, as well as biological samples such as blood, urine, hair, and nail specimens.Dietary habits were assessed using a specially tailored food frequency questionnaire (FFQ) that accounted for the region's distinct dietary patterns.Cohort participants receive monthly follow-ups via phone calls.The study benefits from several factors that enhance its reliability, including the storage of biological samples in both Tehran and France, international collaborations with organizations such as the International Agency for Research on Cancer (IARC), the National Cancer Institute (NCI), and Cambridge University, the establishment of a specialized clinic (Atrak Clinic), adherence to international standards for biological sample preservation, a broad population coverage, and a lengthy follow-up period for study participants. 11ery participant in the Golestan cohort was issued an ID card upon registration.This ID card served as a means for them to seek medical attention at Atrak Clinic in case they experienced digestive symptoms.Atrak Clinic, situated within the primary hospital in Gonbad city, is a specialized gastroenterology clinic established by the Digestive Diseases Research Institute (DDRI).At this clinic, individuals undergo health assessments, and their medical records are kept in the registration system.Furthermore, they receive diagnostic and treatment services at no cost.For all cohort participants who visited Atrak Clinic, personalized files were established, encompassing comprehensive information pertinent to their health and medical history.
Monthly, the databases at Atrak Clinic and the Cancer Registration Center in Golestan province were cross-referenced to identify any instances of cancer among the individuals participating in the cohort. 11 this current study, we utilized the data contained within the

| DALY
DALYs provide a comprehensive measure of the total time lost due to a specific health condition, encompassing both premature death and disability.Originally developed for the World Health Organization's Global Burden of Disease (GBD) study in 1990, DALYs have since evolved into widely accepted standard metric for quantifying the burden of various diseases. 13 calculated the DALY for cancer using procedures derived from those described in the GBD study, which summed the YLL and YLD components.The basic formula is expressed as follows 14 : To calculate the YLL, YLD and DALY, the standard life table of the WHO was used for different age and sex groups.Based on this table, the life expectancy for men was considered equal to 80 years, and for women, 82.5 years.The following formula calculates the YLL. 15

YLL ¼ NL:
In this formula, N is equal to the number of deaths due to UGCs in a certain age and sex group, and L is equal to the standard life expectancy of deceased people of the same age and sex. 16e mean age was used to calculate YLD.The disability weight was estimated using the items described in the GBD and was considered 0.544. 13The duration of the disease was considered from the time of diagnosis to the time of conducting the study.The following formula was used to calculate YLD. 15 YLD ¼ Incidence Â Duration Â DW Disability weight ð Þ : And T-test and analysis of variance were used to compare mean YLL, YLD, and DALY in different age and sex groups.
Patients' data were exported SPSS version 25 software from Excel software.Mean, standard deviation, frequency, and percentage were used to describe quantitative data.

| RESULTS
The majority of patients with UGC were married, had limited formal education, were male, resided in rural areas, and lacked a family history of the disease.Additionally, a significant proportion of the identified patients belonged to the Turkmen ethnic group, and over half of them had a history of drug addiction (Table 1).
The number of patients with UGCs was in 2001, which reached 57 in 2019.The highest number of patients identified was in 2002 (Figure 1).2).
Total number of DALY due to UGCs in the study population was 40 172 (265.2 per 100 000) years (Table 2).
The highest and lowest number of YLL were in the age groups of 60-64 years and 40-44 years, respectively (Figure 3).
The highest number of YLD in men and women were in the age groups above 75 and 70-74, respectively (Figure 4).
The highest and lowest DALY in both sexes were in the age groups of 60-64 years and 40-44 years, respectively (Figure 5).
A statistically significant difference exists in the means of the YLL and DALY indexes between males and females, although no significant difference was observed for the YLD index (Table 2).Furthermore, a statistically significant difference in the means of YLL ( pvalue = .038),YLD ( p-value = .033),and DALY (p-value = .030)indexes was noted across different age groups.

| DISCUSSION
This study aimed to assess the burden of UGCs in the eastern region of Golestan province, Iran.Among the 2481 patients with UGCs, most were male, married, had limited formal education, resided in rural areas, lacked a family history of the disease, had a history of addiction, and were in the age range of 65-74 years.
The  17,18 In recent years, the incidence of UGCs has decreased significantly.For example, in a study between 1997 and 2017, the incidence of gastric cancer decreased by more than 47%. 18This downward trend is observed in many countries worldwide. 19 Iran, previous studies have reported a range of incidence rates for gastric cancer, spanning from as low as 0.1 to as high as 26 cases per 100 000 people.1][22][23][24] The northern regions of Iran, particularly Golestan province, have consistently exhibited a high prevalence of UGCs.Within this province, the disease has demonstrated higher prevalence rates, particularly among the ethnic Turkmen population residing in areas like Gonbad Kavous and Kalaleh. 23In Ghasemi- The findings from the Golestan cohort study have indicated that several risk factors contribute to UGCs.These include an inadequate diet, low socioeconomic status, thermal damage from consuming hot tea, and exposure to carcinogens associated with opium use. 11In their study, Gupta et al. showed that most cancer-related DALYs occur among individuals with lower economic and social status. 28Fitzmaurice et al. highlighted the inadequacies within the healthcare systems of developing countries in delivering care for non-communicable diseases as a contributing factor to the elevated burden of cancer in these nations. 29 et al. argued that UGCs disproportionately affect economically disadvantaged and socially marginalized individuals, primarily because of reduced access to healthcare and education, along with poor living conditions. 30

Kumar et al. conducted an analysis of global trends in
UGCs and found that a significant proportion, specifically threequarters, of these cancers occurred in developing countries in the year 2020. 17Several studies showed the most important risk factors for UGCs in Iran, include drug abuse, alcohol consumption, exposure to environmental pollutants and chemicals, Helicobacter pylori infection, economic and social status, family history of the disease, dietary habits, and age. 11,24,31 the present study, more than 82% of patients were illiterate.
Zarea and colleagues believed that illiterate people are unaware of the importance of annual screening and check-ups.onsequently, they tend to undergo fewer screening tests and are often diagnosed at advanced stages of the disease. 32In their study, Goding Sauer et al.
investigated cancer risk factors in the United States and found that individuals with lower levels of education have a higher prevalence of modifiable risk factors for cancer compared to those with higher education levels.Furthermore, their research demonstrated that individuals with lower educational attainment are less likely to undergo cancer risk screening.For instance, nearly half of women without a college degree were obese, while only one-third of college graduates were obese.This highlights disparities in risk factors and screening behavior related to education level. 33her research results showed that more than 61% of patients are men.This result was similar to previous studies of UGCs in Iran, where the gender ratio of cancer shown a higher incidence among men compared to women. 34,35For example, in the study of Farmanfarma et al. in 2020, the incidence of gastric cancer in men is 74.9 per 100 000 people, while in women, this rate is equal to 4.6 per 100 000 people. 31 Arnold et al also showed in their study in 2020 that globally, gastrointestinal cancers are twice as common in men as in women. 36 Men tend to have greater exposure to environmental pollutants, a higher prevalence of behavioral risk factors, and may receive less preventive care, all of which could contribute to this trend.However, Shadmani et al. showed that while the overall mortality rate in men has been declining in recent years and will remain stable until 2030, it will increase among women in this time frames. 37Therefore, it is necessary to implement interventions focusing on training and raising public awareness among women, emphasizing the importance of annual screening and adopting strategies to improve access to screening tests and healthcare facilities.
In this study, more than 82% of the examined patients were over 55 years old.Also, more than 55% of patients were 65 years old and older.These findings align with the results from Zarea et al.'s study, which demonstrated that the prevalence of gastrointestinal cancer is highest among individuals aged 65 years and older. 32Lin et al.'s study in 2022 showed that the risk of UGCs gradually increases with age. 19study in China showed that people between 65 and 69 years of age are at relatively high risk for UGCs. 30In another study in Rwanda, the average age of esophageal and stomach cancer patients was 54.9 and 56.9 years among men and women, respectively. 38 This study has notable strengths, including its extensive study duration and the use of highly reliable information.However, there are several limitations that should be acknowledged.Firstly, the study lacks information concerning the stage of UGC, the distribution of treatment modalities, and survival outcomes.Moreover, a key limitation is that the study only included the population of two specific cities, which may impact the generalizability of its findings.Caution should be exercised when extending the results to broader populations.

| CONCLUSION
This study has revealed that between 2001 and 2020.Approximately 45% of the patients under examination were in the age group of economic activity, which is typically below 65 years old.This demographic could potentially impose substantial economic costs on the country, both through healthcare expenditures and household expenses related to treatment.Furthermore, over 85% of the patients resided in rural areas, where unhealthy dietary habits and lifestyles, patient files for individuals diagnosed with upper gastrointestinal cancers, which includes esophageal and stomach cancers, spanning the years 2001-2020.A total of 2711 patient cases with UGCs were documented and registered at Atrak Clinic.The selection of all these patients was based on a complete census.Following the exclusion of individuals with incomplete records, we utilized the patient records of 2481 cases.The extraction of patient information from their files was carried out using an Excel-based data extraction form.

T A B L E 1
Patients demographic with UGCs between 2001 and 2020 in Golestan cohort.

1
The number of patients with UGCs in the studied population from 2001 to 2020 in Golestan cohort.

3 4 5
Number of YLL stratified by age groups and sex caused by UGCs in the studied population between 2001 and 2020 in Golestan cohort.Number of YLD stratified by age groups and sex caused by UGCs in the studied population between 2001 and 2020 in Golestan cohort.Number of DALY stratified by age groups and sex caused by UGCs in the studied population between 2001 and 2020 in Golestan cohort.suchas the consumption of hot tea, drug use, and certain detrimental dietary practices like smoked fish consumption, appear to be more prevalent.Consequently, there is a clear need to place greater emphasis on interventions aimed at empowering the population and prioritizing primary prevention measures.